(1/1058) S-16924 [(R)-2-[1-[2-(2,3-dihydro-benzo[1,4]dioxin-5-yloxy)-ethyl]- pyrrolidin-3yl]-1-(4-fluorophenyl)-ethanone], a novel, potential antipsychotic with marked serotonin1A agonist properties: III. Anxiolytic actions in comparison with clozapine and haloperidol.

S-16924 is a potential antipsychotic that displays agonist and antagonist properties at serotonin (5-HT)1A and 5-HT2A/2C receptors, respectively. In a pigeon conflict procedure, the benzodiazepine clorazepate (CLZ) increased punished responses, an action mimicked by S-16924, whereas the atypical antipsychotic clozapine and the neuroleptic haloperidol were inactive. Similarly, in a Vogel conflict paradigm in rats, CLZ increased punished responses, an action shared by S-16924 but not by clozapine or haloperidol. This action of S-16924 was abolished by the 5-HT1A antagonist WAY-100,635. Ultrasonic vocalizations in rats were inhibited by CLZ, S-16924, clozapine, and haloperidol. However, although WAY-100,635 abolished the action of S-16924, it did not affect clozapine and haloperidol. In a rat elevated plus-maze, CLZ, but not S-16924, clozapine, and haloperidol, increased open-arm entries. Like CLZ, S-16924 increased social interaction in rats, whereas clozapine and haloperidol were inactive. WAY-100,635 abolished this action of S-16924. CLZ, S-16924, clozapine, and haloperidol decreased aggressive interactions in isolated mice, but this effect of S-16924 was not blocked by WAY-100, 635. All drugs inhibited motor behavior, but the separation to anxiolytic doses was more pronounced for S-16924 than for CLZ. Finally, in freely moving rats, CLZ and S-16924, but not clozapine and haloperidol, decreased dialysis levels of 5-HT in the nucleus accumbens: this action of S-16924 was blocked by WAY-100,165. In conclusion, in contrast to haloperidol and clozapine, S-16924 possessed a broad-based profile of anxiolytic activity at doses lower than those provoking motor disruption. Its principal mechanism of action was activation of 5-HT1A (auto)receptors.  (+info)

(2/1058) Ergoline derivative LEK-8829-induced turning behavior in rats with unilateral striatal ibotenic acid lesions: interaction with bromocriptine.

LEK-8829 [9,10-didehydro-N-methyl-(2-propynyl)-6-methyl-8- aminomethylergoline bimaleinate] is an antagonist of dopamine D2 receptors and serotonin (5-HT)2 and 5-HT1A receptors in intact animals and a D1 receptor agonist in dopamine-depleted animals. In the present study, we used rats with unilateral striatal lesions with ibotenic acid (IA) to investigate the dopamine receptor activities of LEK-8829 in a model with innervated dopamine receptors. The IA-lesioned rats circled ipsilaterally when challenged with apomorphine, the mixed agonist on D1/D2 receptors. LEK-8829 induced a dose-dependent contralateral turning that was blocked by D1 receptor antagonist SCH-23390. The treatment with D1 receptor agonist SKF-82958 induced ipsilateral turning, whereas the treatment with D2 receptor antagonist haloperidol induced contralateral posture. The combined treatment with SKF-82958 and haloperidol resulted in a weak contralateral turning, indicating the possible receptor mechanism of contralateral turning induced by LEK-8829. Bromocriptine induced a weak ipsilateral turning that was blocked by haloperidol. The ipsilateral turning induced by bromocriptine was significantly potentiated by the coadministration of a low dose but not by a high dose of LEK-8829. The potentiation of turning was blocked either by SCH-23390 or by haloperidol. The potentiation of ipsilateral turning suggests the costimulation of D2 and D1 receptors by bromocriptine and LEK-8829, respectively, whereas the lack of potentiation by the highest dose of LEK-8829 may be explained by the opposing activity of LEK-8829 and bromocriptine at D2 receptors. We propose that the D2 and 5HT2 receptor-blocking and D1 receptor-stimulating profile of LEK-8829 is promising for the treatment of negative symptoms of schizophrenia.  (+info)

(3/1058) Behavioral, toxic, and neurochemical effects of sydnocarb, a novel psychomotor stimulant: comparisons with methamphetamine.

Sydnocarb (3-(beta-phenylisopropyl)-N-phenylcarbamoylsydnonimine) is a psychostimulant in clinical practice in Russia as a primary and adjunct therapy for a host of psychiatric disorders, including schizophrenia and depression. It has been described as a stimulant with an addiction liability and toxicity less than that of amphetamines. The present study undertook to evaluate the psychomotor stimulant effects of sydnocarb in comparison to those of methamphetamine. Sydnocarb increased locomotor activity of mice with reduced potency (approximately 10-fold) and efficacy compared with methamphetamine. Sydnocarb blocked the locomotor depressant effects of haloperidol at doses that were inactive when given alone. The locomotor stimulant effects of both methamphetamine and sydnocarb were dose-dependently blocked by the dopamine D1 and D2 antagonists SCH 39166 and spiperone, respectively; blockade generally occurred at doses of the antagonists that did not depress locomotor activity when given alone. In mice trained to discriminate methamphetamine from saline, sydnocarb fully substituted for methamphetamine with a 9-fold lower potency. When substituted for methamphetamine under self-administration experiments in rats, 10-fold higher concentrations of sydnocarb maintained responding by its i.v. presentation. Sydnocarb engendered stereotypy in high doses with approximately a 2-fold lower potency than methamphetamine. However, sydnocarb was much less efficacious than methamphetamine in inducing stereotyped behavior. Both sydnocarb and methamphetamine increased dialysate levels of dopamine in mouse striatum; however, the potency and efficacy of sydnocarb was less than methamphetamine. The convulsive effects of cocaine were significantly enhanced by the coadministration of nontoxic doses of methamphetamine but not of sydnocarb. Taken together, the present findings indicate that sydnocarb has psychomotor stimulant effects that are shared by methamphetamine while demonstrating a reduced behavioral toxicity.  (+info)

(4/1058) Effect of psychotropic drugs on caudate spindle in cats.

To ascertain whether neuroleptics act on the caudate nucleus itself, the effects of these compounds as well as other centrally acting drugs were examined in relation to caudate spindle and EEG arousal responses (sciatic nerve stimulation) in gallamine-immobilized cats. Haloperidol and chlorpromazine enhanced the caudate spindle at a dose which had no effect on the EEG arousal response. On the other hand, clozapine and a higher dose of chlorpromazine enhanced the caudate spindle, but depressed the arousal response. High frequency stimulation of the sciatic nerve suppressed the caudate spindle. Pentobarbital, biperiden and diazepam, while depressing the arousal response, caused an enhancement of the caudate spindle. Imipramine at a low dose had no effect on either response, whereas at a high dose this drug enhanced the caudate spindle with concomitant depression of the arousal response. From these results, it may be concluded that the enhancing action on the caudate spindle induced by haloperidol and a low dose of chlorpromazine is due to an increase in susceptibility of the caudate nucleus itself. In addition, it is suggested that depression of the activating system is involved in an appearance of the caudate spindle.  (+info)

(5/1058) Comparison of effects of haloperidol administration on amphetamine-stimulated dopamine release in the rat medial prefrontal cortex and dorsal striatum.

Research has shown that there are important neurochemical differences between the mesocortical and mesostriatal dopamine systems. The work reported in this paper has sought to compare the regulation of dopamine release in the medial prefrontal cortex and the anterior caudate-putamen. In vivo microdialysis was used to recover dialysate fluid for subsequent assay for dopamine concentrations. The responses to D2 antagonist (haloperidol) administration, which has been shown to increase impulse-dependent dopamine release, were compared. Results demonstrated a diminished effect of systemic haloperidol administration on dopamine efflux in the prefrontal cortex. The responses to systemic administration of a nonimpulse-dependent, transporter-mediated, dopamine releaser (d-amphetamine) were also contrasted. Results again demonstrated a diminished pharmacological effect in the cortex. The potential interaction of stimulation of these two types of dopamine release was examined by coadministration of these compounds. Haloperidol pretreatment dramatically potentiated the dopamine-releasing effect of amphetamine administration. This effect was observed in both the cortex and the striatum. Subsequent work demonstrated that this effect of haloperidol was mediated by D2-like receptors in the prefrontal cortex. These results are discussed in relation to other neurochemical and neuroanatomical studies demonstrating sparse densities of dopamine transporter sites and dopamine D2 receptors in the cortex compared with the striatum. They demonstrate a functional correlate to the recently reported, largely extrasynaptic localization of dopamine transporter sites in the prefrontal cortex. Furthermore, they demonstrate the existence of cortical D2-like autoreceptors that may normally be "silent" under basal conditions.  (+info)

(6/1058) Molecular and ligand-binding characterization of the sigma-receptor in the Jurkat human T lymphocyte cell line.

The sigma binding site present in the Jurkat human T lymphocyte cell line was investigated. Jurkat cell membranes were found to have a single saturable binding site for [3H]haloperidol, a sigma ligand (dissociation constant, 3.9 +/- 0.3 nM). The binding of [3H]haloperidol was inhibited by several sigma ligands. Northern analysis and reverse transcription-polymerase chain reaction provided evidence for the expression of the recently cloned type 1 sigma-receptor (sigma-R1) in Jurkat cells. The sigma-R1 cDNA cloned from these cells was functional in heterologous expression systems. When expressed in mammalian cells, the cDNA-induced binding was saturable with dissociation constants of 1.9 +/- 0.3 nM for [3H]haloperidol and 12 +/- 2 nM for (+)-pentazocine. The binding of [3H]progesterone, a putative endogenous ligand to sigma-R1, to the Jurkat cell sigma-receptor could be directly demonstrated by using heterologously expressed sigma-R1 cDNA. The binding of [3H]progesterone was saturable, with a dissociation constant of 88 +/- 7 nM. Progesterone and haloperidol interacted with the receptor competitively. Reverse transcription-polymerase chain reaction also produced evidence for the existence of an alternatively spliced sigma-R1 variant in Jurkat cells. This splice variant was found to be nonfunctional in ligand binding assays. This constitutes the first report on the molecular characterization of the sigma-receptor in immune cells.  (+info)

(7/1058) Synergistic interactions between ampakines and antipsychotic drugs.

Tests were made for interactions between antipsychotic drugs and compounds that enhance synaptic currents mediated by alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid-type glutamate receptors ("ampakines"). Typical and atypical antipsychotic drugs decreased methamphetamine-induced hyperactivity in rats; the effects of near or even subthreshold doses of the antipsychotics were greatly enhanced by the ampakines. Interactions between the ampakine CX516 and low doses of different antipsychotics were generally additive and often synergistic. The ampakine did not exacerbate neuroleptic-induced catalepsy, indicating that the interaction between the different pharmacological classes was selective. These results suggest that positive modulators of cortical glutamatergic systems may be useful adjuncts in treating schizophrenia.  (+info)

(8/1058) Stimulation of P-glycoprotein-mediated drug transport by prazosin and progesterone. Evidence for a third drug-binding site.

P-glycoprotein is a plasma membrane protein of mammalian cells that confers multidrug resistance by acting as a broad-specificity, ATP-dependent efflux transporter of diverse lipophilic neutral or cationic compounds. Previously, we identified two positively cooperative drug-binding sites of P-glycoprotein involved in transport [Shapiro, A. B. & Ling, V. (1997) Eur. J. Biochem. 250, 130-137]. The H site is selective for Hoechst 33342 and colchicine. The R site is selective for rhodamine 123 and anthracyclines. Substrate binding to one site stimulates transport by the other. In this paper, we show that prazosin and progesterone stimulate the transport of both Hoechst 33342 and rhodamine 123. Rhodamine 123 and prazosin (or progesterone) in combination stimulate Hoechst 33342 transport in an additive manner. In contrast, Hoechst 33342 and either prazosin or progesterone interfere with each other, so that the stimulatory effect of the combination on rhodamine 123 transport is less than that of each individually. Non-P-glycoprotein-specific effects of prazosin on membrane fluidity and permeability were excluded. These results indicate the existence of a third drug-binding site on P-glycoprotein with a positive allosteric effect on drug transport by the H and R sites. This allosteric site appears to be one of the sites of photoaffinity labeling of P-glycoprotein by [125I]iodoarylazidoprazosin [Safa, A. R., Agresti, M., Bryk, D. & Tamai, I. (1994) Biochemistry 33, 256-265] and is likely not to be capable of drug transport.  (+info)